Abstract
Over the past decade, thiazines, thiadiazoles, and thiohydrazides have attracted increasing attention due to their sedative, antimicrobial, antiviral, antifungal, and antitumor activities. The clinical efficacy of such drugs, as well as the possibility of developing resistance to antimicrobials, will depend on addressing a number of fundamental problems, including the role of membrane lipids during their interaction with plasma membranes. The effects of the eight 1,3- thiazine-, 1,2,3,4- dithiadiazole-, and thiohydrazide-related compounds on the physical properties of model lipid membranes and the effects on reconstituted ion channels induced by the polyene macrolide antimycotic nystatin and antifungal cyclic lipopeptides syringomycin E and fengycin were observed. We found that among the tested agents, the fluorine-containing compound N′-(3,5-difluorophenyl)-benzenecarbothiohydrazide (C6) was the most effective at increasing the electric barrier for anion permeation into the hydrophobic region of the membrane and reducing the conductance of anion-permeable syringomycin pores. A decrease in the membrane boundary potential with C6 adsorption also facilitated the immersion of positively charged syringomycin molecules into the lipid bilayer and increases the pore-forming ability of the lipopeptide. Using differential scanning microcalorimetry, we showed that C6 led to disordering of membrane lipids, possibly by potentiating positive curvature stress. Therefore, we used C6 as an agonist of antifungals forming the pores that are sensitive to membrane curvature stress and lipid packing, i.e., nystatin and fengycin. The dramatic increase in transmembrane current induced by syringomycin E, nystatin, and fengycin upon C6 treatment suggests its potential in combination therapy for treating invasive fungal infections.
Highlights
The growth trend of fungal diseases in the etiology of hospital-acquired and some community-acquired infections and development of pathogen resistance to existing drugs due to the widespread use of broad-spectrum antibiotics and immunosuppressants requires the identification of fungi species that were previously considered non-pathogenic and new antifungal drugs and formulations
Drugs from the group of echinocandins that target Candida spp. and Aspergillus genera are ineffective in fighting many other classes of fungi, and the appearance of strains with reduced sensitivity to echinocandins is an increasing problem as well (Eschenauer et al, 2007)
A widely recognized mechanism of amphotericin B (AmB) action includes ergosterol binding and pore formation, which lead to increased membrane permeability to ions and small organic molecules and cell death (Kasumov et al, 1979; Baginski et al, 2002; Romero et al, 2009; Cohen, 2010)
Summary
The growth trend of fungal diseases in the etiology of hospital-acquired and some community-acquired infections (both superficial and severe visceral mycoses associated with HIV infection and hematologic diseases) and development of pathogen resistance to existing drugs due to the widespread use of broad-spectrum antibiotics and immunosuppressants requires the identification of fungi species that were previously considered non-pathogenic and new antifungal drugs and formulations. Azoles have obvious benefits, such as low cost, limited toxicity, and oral administration, the resistance of pathogenic fungi strains to the most commonly applied azoles, e.g., fluconazole, itraconazole, voriconazole, and posaconazole, is a serious problem (Kontoyiannis and Lewis, 2002; Fera et al, 2009). A widely recognized mechanism of AmB action includes ergosterol binding and pore formation, which lead to increased membrane permeability to ions and small organic molecules and cell death (Kasumov et al, 1979; Baginski et al, 2002; Romero et al, 2009; Cohen, 2010). Systemic treatment with AmB is associated with severe side effects, including nephrotoxicity and hepatotoxicity; its less toxic lipid-associated formulations are used
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